title: Fundamental differences in promoter CpG island DNA hypermethylation between human cancer and genetically engineered mouse models of cancer.
abstract: Genetic and epigenetic alterations are essential for the initiation and progression of human cancer. We previously reported that primary human medulloblastomas showed extensive cancer-specific CpG island DNA hypermethylation in critical developmental pathways. To determine whether genetically engineered mouse models (GEMMs) of medulloblastoma have comparable epigenetic changes, we assessed genome-wide DNA methylation in three mouse models of medulloblastoma. In contrast to human samples, very few loci with cancer-specific DNA hypermethylation were detected, and in almost all cases the degree of methylation was relatively modest compared with the dense hypermethylation in the human cancers. To determine if this finding was common to other GEMMs, we examined a Burkitt lymphoma and breast cancer model and did not detect promoter CpG island DNA hypermethylation, suggesting that human cancers and at least some GEMMs are fundamentally different with respect to this epigenetic modification. These findings provide an opportunity to both better understand the mechanism of aberrant DNA methylation in human cancer and construct better GEMMs to serve as preclinical platforms for therapy development.
authors.affiliation: Division of Clinical Research; Fred Hutchinson Cancer Research Center; Seattle, WA USA; Department of Pediatrics; University of Washington School of Medicine; Seattle, WA USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Diede
authors.affiliation: Division of Human Biology; Fred Hutchinson Cancer Research Center; Seattle, WA USA.
authors.forename: Zizhen
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Division of Human Biology; Fred Hutchinson Cancer Research Center; Seattle, WA USA.
authors.forename: C Chip
authors.initials: CC
authors.lastname: Keyes
authors.affiliation: Division of Human Biology; Fred Hutchinson Cancer Research Center; Seattle, WA USA.
authors.forename: Ashlee E
authors.initials: AE
authors.lastname: Tyler
authors.affiliation: Division of Clinical Research; Fred Hutchinson Cancer Research Center; Seattle, WA USA.
authors.forename: Joyoti
authors.initials: J
authors.lastname: Dey
authors.affiliation: Department of Neurological Surgery; University of California at San Francisco; San Francisco, CA USA; Department of Neurology; University of California at San Francisco; San Francisco, CA USA; Department of Pediatrics; University of California at San Francisco; San Francisco, CA USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Hackett
authors.affiliation: Division of Basic Sciences; Fred Hutchinson Cancer Research Center; Seattle, WA USA.
authors.forename: Katrina
authors.initials: K
authors.lastname: Elsaesser
authors.affiliation: Division of Basic Sciences; Fred Hutchinson Cancer Research Center; Seattle, WA USA; Division of Public Health Sciences; Fred Hutchinson Cancer Research Center; Seattle, WA USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kemp
authors.affiliation: Division of Basic Sciences; Fred Hutchinson Cancer Research Center; Seattle, WA USA; Department of Medicine; University of Washington School of Medicine; Seattle, WA USA.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Neiman
authors.affiliation: Department of Neurological Surgery; University of California at San Francisco; San Francisco, CA USA; Department of Neurology; University of California at San Francisco; San Francisco, CA USA; Department of Pediatrics; University of California at San Francisco; San Francisco, CA USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
authors.affiliation: Division of Clinical Research; Fred Hutchinson Cancer Research Center; Seattle, WA USA; Department of Pediatrics; University of Washington School of Medicine; Seattle, WA USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Olson
authors.affiliation: Division of Clinical Research; Fred Hutchinson Cancer Research Center; Seattle, WA USA; Division of Human Biology; Fred Hutchinson Cancer Research Center; Seattle, WA USA; Department of Neurology; University of Washington School of Medicine; Seattle, WA USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tapscott
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics; D002051:Burkitt Lymphoma / Q000235:genetics; D002528:Cerebellar Neoplasms / Q000235:genetics; D018899:CpG Islands; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics*; D009374:Neoplasms, Experimental / Q000235:genetics*; D011401:Promoter Regions, Genetic
keywords: DNA methylation; cancer; epigenomics; genetically engineered mouse models; medulloblastoma